Core D: Neuropathology PROJECT SUMMARY Mounting evidence suggests that Alzheimer disease (AD) pathology begins decades before the onset of cognitive symptoms, during a 'preclinical' phase. The changes that occur in the brain over the entire course of AD, from the preclinical phase through dementia, are complex; they involve the deposition of amyloid-beta peptide into microscopic plaques, a reactive inflammatory response within the brain (?neuroinflammation?), the formation of neurofibrillary tangles within neurons, and the loss of neurons and their connections (synapses). Within the last decade, building on our advancing knowledge of AD, several ?biomarkers? (biofluid analyses and neuroimaging techniques) have been developed to test for and monitor the course of these changes, and these ?biomarkers? have been applied in clinical trials seeking to evaluate the effectiveness of treatments that target the changes seen in AD. But much about AD remains poorly understood. A better understanding of the disease ? and better ?biomarkers? ? will hasten progress towards an effective treatment for AD. In this effort, studies of postmortem brain tissue are indispensable. Comprehensive brain examination can establish not only whether a person had AD and how advanced that AD pathology had become, but can also detect other neurodegenerative diseases that commonly coincide with AD. Just as important: scientific studies of postmortem brain specimens can facilitate the evaluation of new neuroimaging biomarker compounds in ways that are not possible in living participants, and can reveal new secrets about the pathophysiology of AD. The mission of the Dominantly Inherited Alzheimer Network (DIAN) Neuropathology Core (NPC) is to collect, process, analyze, store, and distribute autopsy brain tissue from study participants to support the scientific projects of DIAN, and other scientists around the world. Towards this end, the NPC examines brains for the amounts and distributions of neuronal loss, gliosis, vascular disease sequela, and deposits of A?, hyperphosphorylated tau, alpha-synuclein, and pTDP-43. These detailed studies enable us to provide appropriate neuropathologic diagnoses to families, and supply appropriate tissues to scientific studies. By providing tissue samples and histopathological data to current DIAN Projects, the NPC will help to: improve our understanding of the atomic structures of the forms of amyloid-beta peptide that appear in AD brain tissue (Project 1); study the impact of different ADAD mutations on the autoradiographic binding patterns of amyloid PET tracer PIB (Project 1); evaluate and compare the autoradiographic binding patterns of tau PET tracers AV- 1451 and MK-6240 (Project 2); and study the complex systems biology of AD (including changes in neurons and glial cells, neuroinflammation, and synaptic loss) using cutting-edge proteomic and molecular techniques (Project 3). Collectively, the findings from these studies will inform the selection of PET tracer compounds to be used in clinical trials, and advance our understanding of AD pathophysiology over the entire course of the disease, from the first ?silent? pathologic changes, through the onset and worsening of dementia.